Amorphous Drug Solubility and Maximum Free Drug Concentrations in Cyclodextrin Solutions: A Quantitative Study Using NMR Diffusometry

Cyclodextrin (CD) has been widely used as a solubilizing agent for poorly water-soluble drugs. In the present study, the effect of CD on the amorphous drug solubility and the maximum thermodynamic activity of the drug in the aqueous phase when the drug concentration exceeded the liquid-liquid phase separation (LLPS) concentration was investigated using three chemically diverse CDs, beta-cyclodextrin (beta-CD), dimethyl-beta-CD (DM-beta-CD), and hydroxypropyl-beta-CD (HP-beta-CD). The amorphous solubility of ibuprofen (IBP) increased substantially linearly with the increase in the CD concentration due to IBP/CD complex formation. Surprisingly, although the crystalline solubility of IBP in the beta-CD solution reached a plateau at beta-CD concentrations above 3 mM (BS-type solubility diagram) because of the limited crystalline solubility of the IBP/beta-CD complex, the amorphous solubility of IBP increased linearly even when the beta-CD concentration was higher than 3 mM. The amorphous solubility of IBP in CD solutions was influenced primarily by the phase separation of the IBP-supersaturated solution to the aqueous phase and the other phase mainly composed of IBP, namely, the IBP-rich phase, via LLPS. NMR spectroscopy revealed that DM-beta-CD was distributed into the IBP-rich phase when the IBP concentration exceeded its amorphous solubility, while beta-CD and HP-beta-CD showed minimal mixing with the IBP-rich phase. NMR diffusometry showed that the maximum free IBP concentration was reduced in the DM-beta-CD solution compared to that in the buffer. The mixing of DM-beta-CD with the IBP-rich phase reduced the chemical potential of IBP in the IBP-rich phase, which in turn reduced the maximum thermodynamic activity of IBP in the aqueous phase. In contrast, the maximum free IBP concentration was unchanged when beta-CD or HP-beta-CD was present. The hydrophobic nature of the DM-beta-CD substituent may contribute to its partitioning into the IBP-rich phase. The present study highlights the impact of CD on the maximum thermodynamic activity of drugs as well as the apparent amorphous solubility of the drug. This aspect should be considered for improving the effective absorption of poorly water-soluble drugs.

Automated summary

Cyclodextrin significantly affects the amorphous solubility of drugs, with DM-beta-CD having a greater impact on the IBP-rich phase.